The cognitive deficits caused by prenatal exposure to alcohol are reflected in the specific functional and structural abnormalities found in brains of alcohol-exposed children. Many of the same molecular and cellular events that shape the early developing brain reoccur later in life during critical periods of plasticity or change. This proposal will examine the impact of alcohol (EtOH) exposure on a signaling pathway that regulates plasticity in both the developing prenatal and adolescent brain. Reelin-Dabi signaling controls lamination and dendritogenesis in the cortex and hippocampus during prenatal development, and separately enhances long-term potentiation (LTP) of memory encoding synapses in the postnatal period. Deficiency in Reelin- Dabi signaling causes brain malformations, mental retardation and epilepsy in humans. We find that EtOH exposure, even acute dose exposure, causes a significant reduction of Dabi protein levels in maturing neurons. Dabi is an adaptor protein that is a component of the Reelin receptor complex and is absolutely required for Reelin signaling. EtOH exposure can drive Dabi levels to -20% of their normal value, levels that are known to cause serious brain malformations during development and likely functional changes in adolescence. This proposal will 1) examine the molecular mechanisms that trigger Dabi suppression after EtOH exposure and then determine the consequences of EtOH-induced Dabi suppression on 2) dendritic growth during the prenatal period and 3) plasticity or long term potentiation in the hippocampus during the postnatal period. The examination of this interaction between EtOH and Reelin-Dabi should provide new insight into key biochemical events that underlie EtOH's negative impacts on neuronal plasticity during the critical stages of embryonic and adolescent brain development.